WHO/BS/ ENGLISH ONLY. EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION Geneva, 29 October to 2 November 2018

Transcription

1 0 0 0 WHO/BS/0. ENGLISH ONLY EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION Geneva, October to November 0 WHO Questions and Answers: Similar Biotherapeutic Products Proposed document to complement the WHO guidelines on evaluation of similar biotherapeutic products, Annex, WHO TRS No., adopted in 00 NOTE: This draft document has been prepared for the purpose of inviting comments and suggestions on the proposals contained therein, which will then be considered by the WHO Expert Committee on Biological Standardization (ECBS). The distribution of this document is intended to bring the proposed WHO document on Questions and Answers on similar biotherapeutic products to the attention of a broad audience and to improve the transparency of the consultation process. The text in its present form does not necessarily represent an agreed formulation of the ECBS. Written comments proposing modifications to this text MUST be received by 0 September 0 using the Comment Form available separately and should be addressed to: Department of Essential Medicines and Health Products (EMP), World Health Organization, 0 Avenue Appia, Geneva, Switzerland. Comments may also be submitted electronically to the Responsible Officer: Dr Hye-Na Kang at kangh@who.int. The outcome of the deliberations of the ECBS will be published in the WHO Technical Report Series. The final agreed formulation of the document will be edited to be in conformity with the second edition of the WHO style guide (KMS/WHP/.).

2 WHO/BS/0. Page of World Health Organization 0 All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any website. Please send any request for permission to: Dr Ivana Knezevic, Technologies Standards and Norms, Department of Essential Medicines and Health Products, World Health Organization, CH- Geneva, Switzerland. knezevici@who.int. The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.

3 WHO/BS/0. Page of WHO Questions and Answers: Similar Biotherapeutic Products Background I. Concept for licensing similar biotherapeutic products QI- What is a similar biotherapeutic product (SBP)? QI- How are SBPs evaluated for licensing? QI- What are the differences between SBPs and generic products? QI- Which products can be approved as SBPs? II. Reference biotherapeutic products QII- What is the reference biotherapeutic product (RBP) mentioned in the biosimilar regulatory framework? QII- What are the criteria for selection of an RBP? QII- Under what circumstances would it be acceptable to use a foreign-sourced RBP? QII- Can the SBP be approved when compared with an RBP which is not available in the domestic market? QII- The guidelines state that the same RBP should be used throughout the entire comparability exercise. Can an RBP from another manufacturing site be used? III. Quality QIII- Should the expression system used in producing an SBP be the same as the one used to produce the RBP? QIII- Should the SBP have the same formulation as the RBP? QIII- Should the SBP have the same delivery device or container closure system as the RBP? QIII- Should the SBP have the same strength as the RBP and how can this be demonstrated? QIII- Should the specifications of the SBP be the same as those of the RBP? QIII- How many batches must be analysed in the comprehensive comparability studies? QIII- What is the role of pharmacopoeial monographs in the evaluation of SBPs? QIII- What is the role of reference standard materials in the evaluation of SBPs? QIII- How should the expiry date of an SBP be established? QIII-0 Are comparability studies in accelerated and stress stability tests needed? QIII- When conducting a comparability exercise, head-to-head characterization studies are required to compare the SBP and the RBP. How much difference or what kinds of differences can be accepted while ensuring a high degree of similarity between the SBP and the RBP?

4 WHO/BS/0. Page of QIII- How comprehensive should the evaluation of glycan structure (i.e. level of details) be? QIII- How can statistical analysis support the demonstration of similarity of an SBP to the RBP in quality evaluation? IV. Nonclinical evaluation QIV- Which general factors should be considered for the planning/conduct of the nonclinical studies for an SBP? Nonclinical in vitro studies QIV- What kind of in vitro studies should be conducted for the nonclinical evaluation of an SBP? QIV- Which specific factors should be observed for the planning/conduct of the nonclinical in vitro studies? Nonclinical in vivo studies QIV- Which factors should be considered when deciding whether in vivo animal studies are required for nonclinical evaluation of a specific SBP? QIV- Which specific factors should be considered in the planning/conduct of in vivo animal studies on pharmacodynamics and/or pharmacokinetics of an SBP? QIV- Which specific factors should be considered in the planning/conduct of in vivo animal toxicity studies for an SBP? QIV- Where no suitable animal model is available, how can the nonclinical comparability exercise be extended? QIV- Under what circumstances/conditions would additional in vivo nonclinical comparability studies be required? V. Clinical evaluation QV- What is the role of clinical evaluation in the SBP development? QV- What is immunogenicity and which factors should be considered in terms of immunogenicity for an SBP? QV- What duration of immunogenicity is required in the clinical studies? QV- How are differences in immunogenicity handled? QV- If the RBP shows a higher rate of anti-drug antibodies than the historical data, what would be the data requirement for the SBP? QV- If the comparability study of efficacy is waived, is a separate immunogenicity study required or could immunogenicity assessment be conducted in a comparative pharmacokinetic/pharmacodynamic study? QV- How can SBPs be approved for indications for which no clinical studies have been conducted? QV- What are the most important points to consider in extrapolating clinical data showing biosimilarity in one indication to other licensed indications of the RBP?

5 WHO/BS/0. Page of 0 0 QV- QV-0 QV- QV- After an SBP has been approved, can a new indication added to the RBP be shared with the SBP? Why are different regulatory decisions on extrapolation reached by different national regulatory authorities (NRA) when using the same regulatory data package? How should inexperienced NRAs deal with differing regulatory decisions of major experienced NRAs? Is there always a need to conduct a clinical study for an SBP? VI. Pharmacovigilance: QVI- Will SBPs be as safe as originator products? QVI- QVI- QVI- QVI- QVI- After an SBP has been approved, is the SBP required to show the maintenance of biosimilarity with its RBP? Would it be beneficial to review/discuss post-marketing commitments from each NRA after extrapolation of indications? If safety information of the RBP (i.e.as the result of adverse events) is amended, how would it be applied to SBPs that are already approved? Can the SBP marketing authorization holder seek approval for a new indication, dosage form or route of administration that is different from the RBP? Should cautions for the use of an SBP be the same with those for the licensed RBP? Authors and acknowledgements Other recommended reading Guidance documents published by the World Health Organization (WHO) are intended to be scientific and advisory in nature. Each of the following sections constitutes guidance for national regulatory authorities (NRA) and for manufacturers of biological products.

6 WHO/BS/0. Page of 0 Abbreviations ADA anti-drug antibody ADCC antibody-dependent cellular cytotoxicity ADCP antibody-dependent cellular phagocytosis CDC complement-dependent cytotoxicity ECBS Expert Committee on Biological Standardization EU European Union FDA (United States) Food and Drug Administration NRA national regulatory authority PD pharmacodynamics PK pharmacokinetics Q&A questions and answers RBP reference biotherapeutic product SBP similar biotherapeutic product WHO World Health Organization

7 WHO/BS/0. Page of Background WHO s Guidelines on evaluation of similar biotherapeutic products (SBPs) (also called biosimilars ), adopted by the WHO Expert Committee on Biological Standardization (ECBS) in 00, have raised awareness of the complex scientific issues related to the licensing of SBPs. However, in some countries and for a variety of reasons, biotherapeutic products have been licensed as generics or as small molecule drugs using data which do not now meet current WHO regulatory expectations. Very little is known about the safety and efficacy of these individual products. Consequently, these products need to be reassessed by national regulatory authorities (NRAs), as described in the WHO guidance document on Regulatory assessment of approved rdna-derived biotherapeutics. In May 0, the Sixty-seventh World Health Assembly adopted a new resolution on access to biotherapeutic products while ensuring their quality, safety and efficacy. One of the requests was for the WHO ECBS to update the 00 guidelines, taking into account the technological advances for the characterization of biotherapeutic products and considering national regulatory needs and capacities. In response, WHO has convened meetings to identify the needs, as well as the parts of the guidelines which should be updated. In April 0, an informal consultation was organized on the possible amendment of the guidelines. All participants from NRAs from both developing and developed countries, as well as those from industry, recognized and agreed that the evaluation principles described in WHO s 00 Guidelines on evaluation of similar biotherapeutic products (SBPs) were still valid, valuable and applicable in facilitating the harmonization of SBP requirements globally. It was therefore concluded that there was no need to revise the main body of the existing guidelines on SBPs. However, it was also agreed that there was a need for additional guidance on the evaluation of monoclonal antibody products as biosimilars, and this guidance was subsequently developed and was adopted by the ECBS 0. In May 0, WHO held another consultation on improving access to and use of similar biotherapeutic products. From the outcome of this consultation, WHO noted that developing a questions and answers (Q&As) document is more appropriate than revision of the guidance content for further clarifying and complementing some areas and points written in the guidelines. These Q&As are produced for guidance only and should be read in conjunction with relevant WHO guidelines. The Q&As are intended to provide clarity to questions that may arise in the use of WHO guidelines. The questions in this document have been selected on the basis of those frequently asked by regulators during the implementation workshops on WHO s Guidelines on evaluation of similar biotherapeutic products (SBPs) in the past years. The intention is to update the Q&As regularly to reflect new developments and issues that arise, but not to address issues of interchangeability, switching, substitution, naming or shortages which are out of the scope of the original guidelines.

8 WHO/BS/0. Page of I. Concept for licensing similar biotherapeutic products: QI- What is a similar biotherapeutic product (SBP)? According to WHOs Guidelines on evaluation of similar biotherapeutic products (SBPs), an SBP is a biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product (RBP). In addition to SBP, a variety of terms such as similar biological medicinal products, biosimilar products, follow-on protein products and subsequent-entry biologics have been used to describe these products. Since the main principles of developing SBPs are the same, definitions of the SBP are complementary to the WHO definition. For example, in the European Union (EU), a biosimilar must be highly similar to its RBP. High similarity means that the characteristics of quality, biological activity, safety and efficacy of the SBP and its RBP have been shown to be comparable to the degree that the drug substance of the SBP can be called a version of the drug substance of the RBP. According to the definition of the United States Food and Drug Administration (FDA), there may be differences between the clinically inactive parts of the SBP and the RBP. However, there should be no clinically meaningful differences in the safety, purity and potency of the product. Based on the above definitions, an SBP is highly similar to an original biotherapeutic product (i.e. RBP) and has been developed and assessed according to the regulatory guidelines that ensure an adequate comparison of the SBP to its RBP. A medicinal product that has not been compared and shown to be similar to a reference product as indicated in the WHO SBP guidelines should not be called similar or SBP (see also the WHO guidance document on Regulatory assessment of approved rdna-derived biotherapeutics. QI- How are SBPs evaluated? The development and evaluation principles for SBPs and products containing new active substances, such as RBPs, are different. The RBP of an SBP has been licensed on the basis of a full registration dossier of the pharmaceutical quality, pharmacology and toxicology, as well as of human safety and efficacy, in its therapeutic indications. The development of SBPs relies not only on producing a product that meets the same quality requirements as any other biotherapeutic, but also on generating additional comparative analytical and functional data showing high similarity to the RBP and allowing subsequent abbreviation of the nonclinical and clinical development. This is possible when the manufacturer can demonstrate that the active substances of the SBP and the RBP are highly similar and, thus, can be expected to have the same quality, safety and efficacy. This is achieved by a comprehensive head-to-head analytical comparison of the SBP and the RBP;

9 WHO/BS/0. Page of these data have to be included and submitted in addition to the pharmaceutical quality part of the SBP. Once the analytical similarity has been established, the nonclinical and clinical studies may be abbreviated and/or refined. The role of the nonclinical and clinical study programme is only confirmatory because the aim of the nonclinical and clinical studies is to demonstrate comparability between the SBP and RBP and not to demonstrate efficacy per se. The extent of the (non)clinical programme depends on the ability to demonstrate structural and functional similarity between the SBP and its RBP. Thus, the development should be a stepwise approach in which the results of the previous tests and studies will guide the next steps. Extensive comparisons will inevitably reveal some differences that may be real, or may just reflect limitations of the analytical/assay methods used. Therefore, the overall assessment of similarity is based on the evaluation of the whole comparability data package consisting of quality, nonclinical and clinical data (also called totality of evidence ). The quality and function of a biotherapeutic product are highly dependent on its manufacturing process. The manufacturing process of a biotherapeutic product, both SBPs and RBPs, is changed several times during its life cycle. Significant changes may have an impact on the product. Therefore, regulatory authorities will require the manufacturer to demonstrate with appropriate tests that the safety and efficacy of the product has not been changed. The requirements of these comparability studies after a manufacturing change are described in WHO s Guidelines on procedures and data requirements for changes to approved biotherapeutic products. Comparability studies may include physico-chemical and structural analyses as well as in vitro functional, often cell-based, tests. For more extensive changes and changes that may have a potential clinical impact, additional nonclinical and clinical studies may be required. Regulators have gained experience over many years of assessing manufacturer changes made to the manufacturing process for numerous biotherapeutics to ensure that the safety and efficacy of the product pre- and post-change is comparable. This experience has enabled the development of the concept of biosimilarity. The general scientific principles of comparability assessment for manufacturing changes are applicable to an assessment of similarity for SBPs. The demonstration of high similarity is based on an extensive head-to-head comparability exercise consisting of comparative stateof-the-art physico-chemical, structural and in vitro functional tests, as well as nonclinical and clinical studies. The clinical experience and established safety profile of the originator products facilitates the development of SBPs. QI- What are the differences between SBPs and generic products? The term generic medicine is used to describe chemical, small molecule medicinal products that are structurally and therapeutically equivalent to an originator product of which the patent and/or data protection period has expired. In contrast, SBPs refer to relatively large and complex molecules of biological origin which are difficult to characterize. The abbreviated development of both generics and SBPs depends on the data of their reference products.

10 WHO/BS/0. Page 0 of 0 0 The demonstration of structural identity and bioequivalence of a generic medicine to the reference product is usually sufficient for the licensing of the generic medicine. However, the approach established for licensing generic medicines through bioequivalent studies alone is not scientifically appropriate for licensing an SBP which requires much more extensive studies. Additional analytical and functional, as well as nonclinical and clinical, studies are needed to demonstrate similarity between an SBP and the RBP. SBPs and RBPs are usually produced in cells that generate a product with some microheterogeneity that is unique to each cell type and manufacturing process. Therefore, SBPs and RBPs, or any other therapeutic protein and their versions after a change in manufacturing process, cannot be shown to be identical. In some countries, for various reasons, biotherapeutic products were licensed as generics or as small molecule drugs using data that do not meet current WHO regulatory expectations. Often little is known about the safety and efficacy of the individual products. These products need to be reassessed by NRAs) as described in the WHO guidance document on Regulatory assessment of approved rdna-derived biotherapeutics. QI- Which products can be approved as SBPs? SBPs should be developed and evaluated according to WHO s Guidelines on evaluation of similar biotherapeutic products (SBPs) or similar national guidelines. The RBP must have been licensed on the basis of full data on quality, safety and efficacy. The development of an SBP to a licensed original biotherapeutic product (i.e. RBP) depends on the ability to characterize and compare their structure and function. To date, SBPs have been developed for well-established and well-characterized biotherapeutic products, such as recombinant DNA-derived therapeutic proteins with a proven record of clinical safety and efficacy. Vaccines, plasma-derived products and their recombinant analogues are beyond the scope of the WHO guidelines on SBPs as recommended the WHO ECBS in 00. However, biosimilar versions of low-molecular-weight heparins, although not proteins, have been licensed in some jurisdictions as SBPs.

11 WHO/BS/0. Page of II. Reference biotherapeutic products: QII- What is the reference biotherapeutic product (RBP) referred to in the biosimilar regulatory framework? An RBP is the comparator for head-to-head comparability studies with the SBP in order to show similarity in terms of quality, safety and efficacy. Only an originator product that was licensed in accordance with WHO s Guidelines on the quality, safety and efficacy of biotherapeutic protein products prepared by recombinant DNA technology on the basis of a stand-alone registration dossier can serve as an RBP. The term does not refer to measurement standards such as international, pharmacopoeial or national standards or reference standards. A manufacturer developing an SBP may be allowed to reduce the nonclinical and clinical data set required for licensure if the similarity of the SBP to the chosen RBP in terms of quality is demonstrated by appropriate comparability studies. QII- What are the criteria for selection of an RBP? The main criteria for the selection of the RBP are mentioned in WHO s Guidelines on evaluation of similar biotherapeutic products (SBPs). The RBP should have been approved on the basis of a complete registration dossier, including safety and efficacy studies in each therapeutic indication. It should be fully identifiable (e.g. brand name, pharmaceutical form, formulation, strength, origin of the reference medicinal product, numbers and age of batches). The RBP should have been marketed for a suitable duration and should have a volume of marketed use in a jurisdiction that has a well-established regulatory framework and principles, as well as considerable experience of evaluation of biotherapeutic products and post-marketing surveillance activities. In general, NRAs require the use of a nationally licensed RBP for the evaluation of the SBP. However, this practice may not be feasible for countries that lack nationally licensed RBPs. In case the RBP is not licensed in a given country, the NRA may set additional criteria for the selection of the RBP licensed or resourced in another country. The RBP should be licensed in another country with a complete dossier according to WHO s Guidelines on the quality, safety and efficacy of biotherapeutic protein products prepared by recombinant DNA technology or corresponding guidelines. The RBP should also have market experience that takes into account a significant duration and magnitude of exposure on the market. The manufacturer of the SBP should justify the use of an RBP that is not licensed locally and the same RBP should be used in all comparability studies of a given SBP. QII- Under what circumstances would it be acceptable to use a foreign-sourced RBP? In general, the analytical and in vitro functional comparability of the SBP and the RBP should be demonstrated by using the locally-licensed and sourced product. The use of a foreign-sourced RBP may be feasible when the manufacturer plans a global development. By using this approach, unnecessary repetition of nonclinical and clinical studies can be avoided.

12 WHO/BS/0. Page of 0 0 The use of a foreign-sourced RBP in nonclinical and clinical studies is possible if justified by information on the relationship of the manufacturers of locally-sourced and foreign-sourced RBP. For instance, the manufacturer may demonstrate that the locally-licensed RBP and the foreign-sourced RBP are versions of the same RBP, based on the same development data, including the same clinical data set. In some jurisdictions, comparability studies, such as analytical or even clinical pharmacokinetic (PK) data, are required to support the use of a foreign-sourced product. In smaller jurisdictions, or in cases where there is no locally-licensed RBP, a foreign-sourced RBP may be used throughout the whole comparability exercise to demonstrate similarity to the SBP. The regulatory requirements in such a situation are described in the response to QII-. QII- Can the SBP be approved when compared with an RBP which is not available on the domestic market? Yes, but it has to be justified. The manufacturers must take advice from the relevant NRA. QII- The guidelines state that the same RBP should be used throughout the entire comparability exercise. Can an RBP from another manufacturing site be used? Yes. Production batches from different manufacturing sites can be used provided that products from all manufacturing sites are approved by the relevant regulatory authority and that all RBP production batches used in the comparability exercise conform to the same specifications.

13 WHO/BS/0. Page of III. Quality: QIII- Should the expression system used in producing an SBP be the same as the one used to produce the RBP? Not necessarily. The expression system (i.e. expression vector and production cells) need not be the same as for the RBP if the expressed protein has the same amino-acid sequence as well as a comparable higher-order structure and post-translational modifications. It is recommended that the manufacturers of SBPs use an expression system similar to that of the RBP where possible, since the cell type influences the pattern of post-translational modifications such as glycosylation. Differences between the RBP and SBP in the level and type of post-translational modifications need to be justified in terms of the potential to have an impact on the potency, safety and efficacy of the SBP. The manufacturers of SBPs should also consider expression system-specific process impurities. In general, a manufacturer of an SBP is not able to use the same clone of production cells as the manufacturer of the RBP. The developers of an SBP must develop their own master cell banks for their production cells. If a company wishes to use a novel expression system this might give rise to different glycosylation patterns and new processrelated impurities, and typically regulators would ask for more clinical immunogenicity data. QIII- Should the SBP have the same formulation as the RBP? Not necessarily, as long as the differences do not have an impact on the quality, safety and efficacy of the SBP, and the SBP and RBP can be demonstrated to be comparable. In addition, the manufacturer should justify potential differences between the formulations of the SBP and the RBP. In general, the formulations should be state-of-the-art with regard to stability, compatibility, integrity and impact on activity and strength of the active substance. It is important to justify the lack of adverse impact on the relative efficacy and safety of the SBP if a different formulation and/or container/closure system is used especially any material that is in contact with the medicinal product. The aim of the biosimilar comparability exercise is to demonstrate that the SBP and the RBP chosen by the manufacturer are comparable. QIII- Should the SBP have the same delivery device or container closure system as the RBP? No, it is not necessary for an SBP to have the same delivery device or container closure system as the RBP. The lack of any adverse impact of the delivery device/container closure system on quality, safety, efficacy and usability should be demonstrated. The manufacturer of an SBP should demonstrate that the product remains stable over long-term storage when stored in the chosen container closure systems.

14 WHO/BS/0. Page of Thus it is possible, for instance, to use a different delivery device, such as pre-filled syringe or autoinjector, even if the RBP has only a vial provided that the products are shown to be comparable. QIII- Should the SBP have the same strength as the RBP and how can this be demonstrated? Yes. In general, an SBP should have the same concentration of drug substance as the RBP. The total content of the drug substance per dosage form should be defined by the posology of the RBP and should allow the appropriate application. A difference in the total content of SBP and RBP should be justified. If needed, additional data should be provided. Any difference should not compromise safety. The total content and concentration should be expressed by using the same measurement system as the RBP (i.e. mass units or units of activity). QIII- Should the specifications of the SBP be the same as those of the RBP? The specifications control the most important RBP and SBP quality attributes concerning identity, purity, potency and molecular heterogeneity. Nevertheless, specifications of RBP and SBP are likely to be somewhat different because of different manufacturing processes and analytical methods. Thus, the specifications reflect the experience of the manufacturer s own product. The specifications should be based on WHO s Guidelines on the quality, safety and efficacy of biotherapeutic protein products prepared by recombinant DNA technology. It should be noted that pharmacopoeial monographs provide only minimal requirements. It is expected that the specifications of an SBP do not allow significantly wider batch-to-batch variation than found for the RBP during the quality comparability exercise. QIII- How many batches must be analysed in the comprehensive comparability studies? The analysis of multiple batches of the RBP by the manufacturer is necessary for developing an optimal manufacturing process for a candidate SBP. For this purpose, the manufacturer of an SBP needs to collect a representative set of batches of the RBP over an extended period to justify comparability ranges for critical quality attributes. The relevance of the ranges should be discussed, taking into account the number of RBP batches tested, the quality attributes investigated, the age of the batches at the time of testing, and the evolution of quality attributes over time as well as the test method used. The age of the different batches of the RBP (relative to the expiry dates) should also be considered when establishing the target quality profile. At the next stage, comprehensive head-to-head physico-chemical, structural and in vitro functional comparisons are performed for multiple representative batches of RBP and SBP to

15 WHO/BS/0. Page of confirm representative and comparable quality profiles. It may not be possible to set a definite number for batches of the comprehensive comparability exercise. The number of batches needed to show similarity of each quality attribute and to establish the range of SBP specifications should be sufficient to allow a meaningful comparison with the RBP. The manufacturers may request advice from the relevant regulatory authority on the appropriate number of batches when preliminary results from the degree of variability have been obtained. Where several strengths or presentations are available, their selection should be appropriately justified. QIII- What is the role of pharmacopoeial monographs in the evaluation of SBPs? Pharmacopoeial monographs are public standards which include quality requirements for medicinal products and their constituents. Monographs for biotherapeutic products have been issued in various jurisdictions. An SBP must show the same level of compliance with a pharmacopoeial monograph as the RBP. However, compliance with pharmacopoeial monographs will not be sufficient to demonstrate biosimilarity. QIII- What is the role of reference standard materials in the evaluation of SBPs? WHO provides International Standards and Reference Reagents, which serve as primary reference standards of defined biological activity expressed in an international unit (IU) or unit (U). They are used either to calibrate assays directly or to calibrate secondary standards (e.g. pharmacopoeial and national reference standards) or manufacturers working standards. When available, manufacturers can use international/pharmacopoeial reference standards and reagents for qualification and standardization of the tests used to characterize and quantify RBP and SBP. For example, the potency (expressed, for instance, in units or international units [IU]) is the quantitative measure of biological activity based on an attribute of the product. The potency of each batch of the drug substance and the final dosage form should be established by using, wherever possible, an appropriate national or international reference material which is normally calibrated in units of biological activity such as IU. In the absence of such preparations, an approved in-house reference preparation may be used for assay standardization. Many biological products are labelled and dosed in terms of mass units rather than potency units. For such products, the reference standard (in-house, national or international) may be used to calibrate the working reference standard and the corresponding bioassay used to confirm product quality. In these situations, quality determination of bioactivity is normally expressed in percentage relative terms rather than in units and is not used for product labelling. See: (accessed July 0).

16 WHO/BS/0. Page of However, these reference standards are distinct entities and cannot be used instead of the RBP for demonstration of comparability. QIII- How should the expiry date of an SBP be established? The expiry date of an SBP is based on the SBP stability data which defines its shelf-life and is independent of the RBP. The shelf-life of the SBP should be justified on the basis of full real-time and real-temperature stability data obtained according to the relevant guidelines, namely WHO s Guidelines on the quality, safety and efficacy of biotherapeutic protein products prepared by recombinant DNA technology and the ICH QC guideline on Quality of biotechnological products: stability testing of biotechnological/biological products. QIII-0 Are comparability studies in accelerated and stress stability tests needed? Stability testing of SBPs should comply with the relevant guidelines, namely: WHO s Guidelines on the quality, safety and efficacy of biotherapeutic protein products prepared by recombinant DNA technology and the ICH QC guideline on Quality of biotechnological products: stability testing of biotechnological/biological products. Stability studies on the drug product should be carried out in the intended drug product container closure system. Real-time/real-temperature stability tests will determine the conditions for storage and the shelf-life of the SBP. These conditions may or may not be the same as those of the RBP. Comparative real-time, real-temperature stability studies between the SBP and RBP are not required. Comparative accelerated stability tests not only provide important information on degradation pathways of the active substance and the suitability of the formulation and the container closure system but may also uncover differences between the degradation profiles of the SBP and RBP. Results obtained from the studies may show that additional controls should be used in the manufacturing process and during shipping and storage in order to ensure the integrity of the product. Stress stability testing is necessary for an SBP in order to further investigate appropriate conditions for shipping and storage unless these conditions are covered by accelerated stability studies. In general, comparative stress testing of SBP and RBP does not provide added value. However, depending on the potential degradation mechanism of the molecule, stress conditions (e.g. high/low ph, humidity, oxidation) may reveal differences between the degradation profiles of the SBP and RBP. QIII- When conducting a comparability exercise, head-to-head characterization studies are required to compare the SBP and its RBP. How much difference or

17 WHO/BS/0. Page of what kinds of differences can be accepted while ensuring a high degree of similarity between the SBP and its RBP? The conclusion of high similarity is based on evaluation of the whole data package from quality, nonclinical and clinical parameters and not on an individual variable or physicochemical test. The regulators may use their previous experience, generated for instance from changes introduced into manufacturing processes for the RBP, to understand the functional and clinical impact of a particular physico-chemical difference between the SBP and its RBP. The results of physico-chemical tests should always be interpreted in the light of the performance of a particular analytical method and the batch-to-batch variability of the results. When available, orthogonal analytical techniques should always be used to strengthen the evaluation of comparability. In vitro, usually cell-based, functional assays may be helpful in understanding the significance of a difference detected in the analytical testing. It is important to understand the factors that have an impact on the functional tests. The sensitivity of some of the functional tests, such as reporter gene-based assays, has been increased to the degree that they do not correspond to the physiological situation. In these situations, the manufacturer needs to consider the significance of the results and understand the difference between a robust assay for release and a bio-analytical assay. It is also important to consider other tests that may better reflect the physiological situation. Tests using cells from a specific patient population may also be helpful for interpretation of the observed difference. In general, in vitro functional tests are more sensitive than clinical studies at detecting differences between the SBP and RBP. Results of physico-chemical and structural tests should be considered in planning the clinical comparability programme, especially in PK, pharmacodynamics (PD) and immunogenicity studies. The PK of the SBP and RBP are often compared in single-dose studies involving healthy volunteers, when this is appropriate and depending on the nature of the treatment. The comparability range in the primary PK parameters should be defined and justified prior to conducting the study. The criteria used in the demonstration of bioequivalence of orally administered and chemically synthesized small molecules i.e. 0% confidence interval (CI) of ratios of SBP to RBP are often used for comparative PK studies of SBPs and RBPs in the absence of relevant historical data. If the PK comparability criteria are met but the exposure to SBP is significantly lower or higher, meaning that the CI of the SBP is entirely within either the higher or the lower side of the equivalence range, a root cause analysis and possibly new data could be needed. It is recommended that steady state PK should be measured in the repeat-dose safety and efficacy studies. This may mitigate concerns of some PK differences observed after a single-dose study. The equivalence design is recommended for confirmatory efficacy and safety studies. Noninferiority design may be used if superiority can be excluded. In both cases, the acceptance range is defined by previous clinical trials with the RBP and the difference is not clinically meaningful.

18 WHO/BS/0. Page of QIII- How comprehensive should the evaluation of glycan structure (i.e. level of details) be? A glycoform is an isoform of a protein that differs from others only with respect to the number or type of attached glycans. The biotechnological manufacturing process of a given glycoprotein is sensitive to culture conditions, which may lead to production of different glycoforms in spite of the same glycosylation machinery. This glycoform pattern may to some extent vary from batch to batch. In addition, production cells from different species may produce qualitatively different glycans that should be identified and justified, especially if such glycan does not exist in humans. For glycoproteins, carbohydrate structures should be thoroughly compared, including the overall glycan profile, site-specific glycosylation patterns and site occupancy. The extent of the comparative analysis of the glycoform patterns of the SBP and RBP depends on knowledge about the glycoform pattern of the RBP and the functional role of different glycoforms. Knowledge regarding the variation in the glycoform pattern between batches of the RBP will help in assessment of differences between the SBP and RBP. Differences in the glycans and glycan profiles may have an impact on the structure, potency, PK, safety and efficacy of a product. For instance, sialylated, afucosylated and mannosecontaining structures may display clinically significant variations. Monoclonal antibodies are glycoproteins with glycosylation sites in the Fc portion of the heavy chains, with further possible glycosylation sites depending on the type of molecule. Monoclonal antibodies display several glycoforms that have different functional properties, such as differences in binding to Fc-receptors and complement. Therefore, a thorough analysis of the glycans attached to the Fc-protein backbone is necessary. These data, together with various binding and cell-based functional tests, will be crucial in the demonstration of comparability of an SBP and its RBP. Glycans are rarely immunogenic. However, glycans that are not normally present in humans may be immunogenic. For instance, alpha-gal-, - gal that occurs on the carbohydrate moiety of proteins produced by some mammalian but not human cells may trigger serious hypersensitivity reactions in patients. QIII- How can statistical analysis support the demonstration of similarity of an SBP to the RBP in quality evaluation? Statistical methods have a crucial role to play in interpretation of comparative clinical data, especially PK and efficacy. The role of statistics in evaluation of biosimilarity is less clear with regard to the interpretation of results of comparative physico-chemical, structural and in vitro functional tests, and requires a different approach from that applied when analysing clinical data. Statistical methods usually deal with means. The means may change within the acceptability range. Nevertheless, in some jurisdictions it has been suggested that statistical analyses of comparability data should be conducted in order to evaluate analytical similarity. Using a

19 WHO/BS/0. Page of 0 descriptive statistical approach to establish ranges for quality attributes in the context of comparability is generally more widely accepted. The establishment of similarity by statistical analysis may be influenced by the number of batches and observations, uncertainty regarding the clinical impact of an attribute and distribution of results, performance of the assays, source and age of the batch etc. In conclusion, the use of statistics in defining comparability is still at an empirical stage in most jurisdictions. It is important to realize, however, that statistical tools, while helpful in supporting conclusions about similarity, should not be used as the sole basis for decision-making on biosimilarity for marketing authorization approval which should be based on evaluation of the whole data package for each of the quality, nonclinical and clinical parameters.

20 WHO/BS/0. Page 0 of 0 IV. Nonclinical evaluation: QIV- Which general factors should be considered for the planning/conduct of the nonclinical studies for an SBP? The nonclinical development of SBPs has evolved from merely abbreviated versions of the nonclinical development of original medicinal products to development programmes tailored to the specific features of SBP development. Initially, significant emphasis was put on in vivo comparative nonclinical studies and the original WHO Guidelines on evaluation of similar biotherapeutic products (SBPs) required at least a head-to-head repeat-dose toxicity study. WHO s newer Guidelines on evaluation of monoclonal antibodies as similar biotherapeutic products (SBPs) promote a stepwise nonclinical development starting from demonstration of the physico-chemical and in vitro functional comparability before proceeding to the analysis of remaining uncertainties. If in vivo studies are considered to be indicated, the developer should clarify the availability of relevant animal models. If the drug substance of candidate SBP shows specific pharmacological activity only in great apes, the developer should seriously weigh the need for in vivo studies to avoid pharmaco-toxicological testing in these species. A consultation with the relevant NRA is recommended.

21 WHO/BS/0. Page of Nonclinical in vitro studies QIV- What kind of in vitro studies should be conducted for the nonclinical evaluation of an SBP? The in vitro nonclinical studies should be comparative and should measure relevant biological activities of the drug substance. It is recommended that the tests are complementary or orthogonal in order to support the interpretation of results. Together, these assays should cover the whole spectrum of pharmacological aspects with potential clinical relevance for the RBP and for the product class. The manufacturer should discuss to what extent the in vitro assays used are representative/predictive of the clinical situation in terms of current scientific knowledge. Typically, receptor-binding assays and cell-based functional assays are used to compare the functions of the SBP and RBP. The developer should justify the relevance, sensitivity and discriminatory capability of the tests by submitting qualification and or validation studies using the RBP and SBP. Test results should be given in units of activity calibrated against an international or national reference standard, where available. For instance, monoclonal antibodies have several functionally active sites. Assays are available to measure the binding affinity and activity of the monoclonal antibodies as well as cell-based functional assays for each active site. The standard assays can be tailored to better reflect the physiological or pathological conditions in a particular therapeutic indication. A detailed analysis of the biological activity, including Fab- and/or Fc-mediated functions, such as ability to bind to different isoforms of Fc gamma and neonatal Fc receptors and to complement Cq, should be provided whether or not they are considered essential for the therapeutic mode of action. The absence of a mode of action should be considered by the SBP developer, although this may not require an extensive analytical demonstration and may be assessed via cell-based or binding assays. The corresponding cell-based functional assays, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important as they may play different roles in different therapeutic indications. Where available, international reference standards can be used to support bioassay, characterization, calibration and performance. See also QIII-. QIV- Which specific factors should be observed in the planning/conduct of the nonclinical in vitro studies? It is important to understand what is known about the mechanism of action of the molecule for the selection of the relevant tests for the biological activity. The quality comparability studies may reveal differences that may have an impact on clinical performance, such as PK or efficacy. The nonclinical in vitro studies should be sensitive, specific and sufficiently discriminatory to show any potential differences which, according to current scientific knowledge, could be of potential clinical relevance. Some assays used in the quality

22 WHO/BS/0. Page of assessment may be utilized to inform nonclinical studies. In these cases, the clinical relevance of these assays should be justified. Since in vitro assays may often be more specific and sensitive for detecting differences between SBP and RBP than studies in animals, such assays can be considered paramount for the nonclinical biosimilar comparability exercise.

23 WHO/BS/0. Page of 0 Nonclinical in vivo studies QIV- Which factors should be considered when deciding whether in vivo animal studies are required for nonclinical evaluation of a specific SBP? On the basis of the totality of available quality and nonclinical in vitro data and the extent of residual uncertainty about the similarity of SBP and RBP, nonclinical in vivo studies may not be required. If the quality-comparability exercise and nonclinical in vitro studies are considered satisfactory and no issues that would prevent direct entrance into humans are identified, in vivo animal studies may be considered unnecessary. In some jurisdictions, legislation requires the application of the R (Reduction, Refinement and Replacement of animal experiments) principle in product development in order to reduce the suffering of animals. In particular, studies with non-human primates should be avoided if possible. In vivo animal studies should be considered only when it is expected that such studies would provide relevant additional information. In general, the additional value of in vivo nonclinical studies for the demonstration of comparability of SBP and RBP is questionable when previous physico-chemical, structural and in vitro functional tests have demonstrated the similarity of the SBP and RBP. A number of factors reduce the need for in vivo studies in the development of an SBP: 0 The risk of first-in-man use of an SBP can usually be estimated on the basis of knowledge about the clinical safety profile of the RBP and the outcome of the physicochemical, structural and in vitro functional tests with the SBP. Most toxic effects of therapeutic proteins are related to an exaggeration of their known pharmacological effects. The functional activity of a biotherapeutic drug substance is often species-specific, making it difficult to identify a suitable animal species. Human drug substances are often immunogenic in conventional animal models due to species-specificity, which prevents or hampers the interpretation of repeat-dose animal studies 0 Conventional animal models are often not sensitive enough to detect small differences. QIV- Which specific factors should be considered in the planning/conduct of in vivo animal studies on pharmacodynamics and/or pharmacokinetics of an SBP? PK studies with the SBP should be justified on the basis of RBP data and the interference of anti-drug antibodies. If product-inherent factors that have an impact on PK and/or biodistribution (such as glycosylation or pegylation) cannot be characterized sufficiently at a quality and in vitro level, the manufacturer should carefully consider if in vivo animal PK and/or PD studies should be performed in advance of clinical PK/PD testing. Since relevant PK/PD data are